Gastrointestinal Tract

Introduction

The gastrointestinal tract is a long tube that mechanically and enzymatically digests food into small molecules, then absorbs small molecules and electrolytes, and processes and excretes material that cannot be absorbed. Different segments of the gastrointestinal tract perform different functions:

• Stomach: mechanical disruption of food and some enzymatic digestion
• Small intestine: enzymatic digestion and solubilization into small molecules and absorption of small molecules
• Large intestine (colon): processing of unabsorbed material into waste

Other organs, such as the liver and pancreas, contribute enzymes and other material to the gastrointestinal tract that help with digestion and solubilization of food. These organs will be discussed in a different session.

Basic Organization of the Gastrointestinal Tract

Although different sections of the GI tract have different functions, the basic architecture of the GI tract is similar along its entire length.

The wall of the GI tract comprises several distinct structural and functional layers that are found in all sections of the GI tract. The inner most layer of the wall of the GI tract is the mucosa. The mucosa consists of a layer of epithelium which is in direct contact with the contents in the lumen of the GI tract. At different points along the GI tract the epithelium enzymatically digest food or absorbs the released nutrients. The epithelium sits on a basement membrane. Beneath the basement membrane is a thin layer of connective tissue called the lamina propria. The lamina propria contains blood vessels and lymphatics and in certain sections of the GI tract, large aggregates of immune cells localize to the lamina propria.

A thin layer of smooth muscle called the muscularis mucosa sits beneath the mucosa.

The layer beneath the muscularis mucosa is called the submucosa. The submucosa is a thick layer of connective tissue that contains arteries, veins, lymphatics and in some segments of the GI tract, nervous tissue.

The muscularis externa surrounds the submucosa and is composed of two muscle layers: an inner layer in which the smooth muscle cells are arranged circumferentially around the GI tract and an outer layer in which the smooth muscle cells are arranged longitudinally along the GI tract. When the inner layer of smooth muscle contracts, the diameter of the gastrointestinal tract decreases. When the outer layer contracts, that region of the gastrointestinal tract shortens. The coordinated contraction of these two layers generates peristalsis which propels the contents of the GI tract in one direction, mechanically grinds food in the stomach and mixes food with digestive enzymes in the small intestine.

Lastly, the outer most layer of the GI tract is the adventitia which consists of connective tissue containing blood vessels, nerves, and fat. In the portions of the tract within the peritoneal cavity, it is lined by the mesothelium.

These four layers can be identified in most gastrointestinal segments, although different sections have important structural variations that can provide clues to their functions. The greatest structural and functional variations occur in the mucosal layers, specifically the epithelium.

There are four distinct types of mucosa in the gastrointestinal tract:

• Protective mucosa is characterized by a stratified squamous epithelium and is found in the oral cavity, pharynx, esophagus, and anal canal.
• Secretory mucosa contains cells that are responsible for the secretion of digestive enzymes and acid and is found exclusively in the stomach.
• Absorptive mucosa is responsible primarily for absorbing digested nutrients and is found along the entirety of the small intestine.
• Absorptive mucosa primarily involved in water absorption and electrolyte balance is found in the large intestine.

A change in mucosa also involves a transition in the type and/or function of the epithelium. Unlike the lung where the epithelium undergoes gradual transitions from pseudo-stratified to columnar to cuboidal to squamous, the changes in epithelia in the gastrointestinal tract can be abrupt. For example, the transition from esophagus to stomach has a sharp change in epithelia from stratified squamous to simple columnar (see below).

Four junctions in the GI tract that are characterized by abrupt changes in the mucosal lining:

• Gastro-esophageal junction at the transition from esophagus to stomach
• Gastro-duodenal junction at the transition from stomach to small intestine
• Ileo-cecal junction at the transition from small intestine to large intestine
• Recto-anal junction at the transition from rectum to anus

The first three junctions listed above have a sphincter of smooth muscle that controls the passage of material across the junction.

Mucosal Surface Area

Because the epithelia of the mucosa throughout most of the gastrointestinal tract is either secreting or absorbing material, a large surface area is critical to increase the capacity of the epithelia.

The epithelia will use two basic structures to increase its surface area. One is glands where the epithelia invaginates toward and occasionally into the sub-mucosal layer. Glands are found in the stomach, small intestine and colon. The second structure involves outward folding into the lumen of the gastrointestinal tract of the mucosal and even sub-mucosal layer. These structures are found in the small intestine.

Segments of the Gastrointestinal Tract

Esophagus

The esophagus is a muscular tube that transports food from the pharynx to the stomach. It is lined by a stratified squamous epithelium and has a prominent muscularis mucosa and thick muscularis externa. The muscularis externa of the esophagus is unique in that it transitions from striated to smooth muscle over the length of the tube. The esophagus ends in the gastro-esophageal junction.

The gastro-esophageal junction is notable because the epithelium transitions from stratified squamous in the esophagus to simple columnar epithelium in the stomach. The lower esophageal sphincter is a distinct layer of smooth muscle that separates the esophagus from the stomach. The sphincter allows coordinated movement of food from the esophagus into the stomach while preventing reflux of acidic gastric fluids into the esophagus. The epithelium of the stomach has physical and biochemical mechanisms to protect itself from acid, but esophageal epithelium lacks those properties. Consequently, sustained reflux of gastric contents into the esophagus damages the esophageal epithelium.

Stomach

The stomach mechanically and chemically digests food. A thick muscularis externa which includes an additional third layer of smooth muscle creates a churning action in the stomach that mechanically disrupts food. The epithelium lining the stomach releases enzymes and acid that chemically digest food. The mixture of food, enzymes and acid generate a fluid mass called chyme.

The stomach is functionally divided into four functional regions: cardia, fundus, body and antrum. Each region performs a different physiological function and has an unique cellular profile in its epithelium that mediates its function. The structure and function of some of these regions are described below. Note that the pyloric sphincter controls passage of chyme from the stomach into the duodenum which is the initial segment of the small intestine.

The slide below shows the structure of the stomach lining under the light microscope. The layers of the stomach wall follow the basic plan described above. The epithelium of the mucosal layer forms gastric glands that produce acid and enzymes that help digest food. The submucosa is composed of loose connective tissue with some blood vessels. In a non-distended state, the stomach mucosa is found in prominent folds called rugae. Rugae allow for distension of the stomach after a large meal. The stomach is distinct from other segments of the GI tract in having three layers of smooth muscle in the muscularis externa. In addition to the inner circular and outer longitudinal layers, there is an oblique layer that sits between the submucosa and inner smooth muscle layer. The three layers of muscle generate powerful churning of the stomach contents to facilitate digestion.

Gastric Glands

The functional unit of the stomach is the gastric gland which contains secretory cells that release enzymes or acid into the lumen of the stomach and endocrine cells that mediate communication between the sections of the stomach to regulate the activity of the secretory cells in the epithelium. The endocrine cells also release hormones that regulate the activities of cells in other organs.

A gastric gland begins at the gastric pit which opens to the lumen of the stomach. From the pit the gland invaginates to form the isthmus and neck that lead deepest portion of the gland called the base. Note the muscularis mucosa along the base of the glands. The lamina propria resides beneath epithelial cells that compose the glands.

Cells of Gastric Glands

The cellular composition of the epithelium that forms the glands varies between sections of the stomach. The major cells in the glands are described below.

Mucous Cells

Mucus-secreting cells are found in the glands in all sections of the stomach. They appear pale and contain obvious mucous droplets. The cells are found prominently in the gastric pits and neck. The cells secrete mucus and bicarbonate ions, both of which protect the stomach epithelium from the damaging effects of acid. Mucus coats the surface of stomach epithelium and traps bicarbonate which neutralizes acid in the stomach before it can damage the epithelium.

Parietal Cells

Parietal cells secrete hydrochloric acid and intrinsic factor, which is important for the absorption of vitamin B12 in the ileum. Hydrochloric acid creates a low pH environment in the lumen of the stomach which serves two main functions. The first is to activate digestive enzymes such as pepsin. A low pH environment is also inhospitable to bacteria and therefore limits proliferation of bacteria and the risk of infection.

Parietal cells are usually found in the isthmus region of the gastric gland. In H&E-stained samples, parietal cells have a characteristic "fried-egg" appearance, with a basophilic, centrally located nucleus and a rather eosinophilic cytoplasm. Parietal cells are found exclusively in the body section of the stomach.

The apical surface of parietal cells forms a narrow channel called a canaliculus. Secretion of acid and water into the canaliculus flow out of the canaliculus, through the mucus layer and into the lumen of the gastric gland. This narrow jet of parietal cell fluid that penetrates the mucus layer is thought to prevent the bicarbonate in the mucus from neutralizing the acid in the fluid.

To secrete acid, parietal cells express the H-K pump in their apical membranes which moves hydrogen ion from the cytoplasm to lumen of the gland while taking up potassium from the lumen. Potassium channels in the apical membrane allow potassium to recycle. Parietal cells generate cytosolic hydrogen ion through carbonic anhydrase which catalyze the conversion of CO₂ and H₂O to H⁺ and HCO₃^-. The bicarbonate from the reaction is released across the basal membrane through the Cl^- HCO₃^- exchanger. Cl^- diffuses across the apical membrane through the CFTR channel to maintain electroneutrality with secreted H⁺.

Although not shown in the above diagram, parietal cells contain Na⁺-K⁺ pumps and NKCC2 channels in their basolateral membranes.

Parietal cells increase acid production before and during eating. Three molecules are primarily responsible for stimulating parietal cells to increase secretion of HCl.

• Acetylcholine is released by the vagus nerve onto the surface of parietal cells.
• Histamine is produced by endocrine cells (ECL) in the body region of the stomach. Histamine acts in a paracrine fashion. ECL cells are described below.
• Gastrin is produced by G cells in the antral region of the stomach and the duodenum (initial segment of the small intestine).

All three molecules bind G-protein coupled receptors on the surface of parietal cells. The receptors stimulate pathways that increase cytosolic calcium and activate downstream protein kinases (e.g. Protein Kinase A and Protein Kinase C), all of which ultimately increase in acid production.

To increase acid production, parietal cells increase the surface area of their apical membrane. In a basal or resting state, parietal cells produce small amounts of acid because there are few H-K pumps in the apical membrane. Within their cytoplasm, parietal cells in a basal state contain many tubular and vesicular organelles near the apical membrane. These organelles contain a high concentration of H-K pumps in their membranes. Upon stimulation by the acetylcholine, histamine and/or gastrin, the organelles fuse with the apical cell membrane to increase its surface area and the number of H-K pumps in the cell membrane.

In addition to acting directly on parietal cells, acetylcholine and gastrin also stimulate ECL cells to produce histamine. Thus, acetylcholine and gastrin have both direct and indirect effects on acid production.

Acid production by parietal cells can also be reduced. Another type of ECL cell called D cells are found in the body and antrum of the stomach. These cells release somatostatin which binds a G-protein coupled receptor on the surface of parietal cells. The receptor is linked to an inhibitory G_αi which counteracts the effects of the stimulatory G_αs on adenylyl cyclase that is activated by histamine.

What triggers release of acetylcholine, gastric and histamine? Stimulation of acid production proceeds in three phases: cephalic, gastric and intestinal. Cephalic phase is associated with the sight, smell, taste and even thought of food. Swallowing is also part of the cephalic phase. Stimuli in the cephalic phase trigger acid production via the vagus nerve and its release of acetylcholine.

The gastric phase stimulate acid production through physical and chemical mechanisms. The entry of food into the stomach causes distention which triggers the vagus nerve to release acetylcholine. In addition, the presence of digested protein and amino acids in the antrum region of the stomach stimulates G cells to release gastrin.

Lastly, in the intestinal phase, digested protein and amino acids trigger G cells in the duodenum to release gastrin.

The gastric phase also decreases acid production. Low pH in the antral region stimulates D cells to release somatostatin which inhibits acid production in parietal cells as described above.

Chief Cells

Chief cells are found in the base of the gastric glands and produce pepsinogen, which is stored in large apical secretory granules. After pepsinogen is secreted, it is converted by the acidic environment of the stomach to pepsin which is an active protease. Chief cells have a basally located nuclei and a basophilic cytoplasm with abundant rough endoplasmic reticulum and many secretory granules that contain pepsinogen. These fuse with the cell membrane to release pepsinogen into the lumen of the gastric gland.

Both acetylcholine and gastrin stimulate chief cells to release pepsinogen by activating pathways that increase cytosolic calcium.

Endocrine cells.

The mucosa of the gastric glands contains numerous different endocrine cells that primarily regulate the activity of parietal cells. The mucosa in the body section contains enterochromaffin-like (ECL) cells that produce histamine. ECL cells are typically found in the basal third of gastric glands. The mucosa of the antrum contains G cells that secrete the peptide hormone gastrin into the blood stream. The antrum also contains D cells that release somatostatin which inhibits acid secretion by parietal cells.

Stem cells divide to replace the other cells in the gastric glands. They are located primarily in the neck of the glands.

Regions of the Stomach

The three different regions of the stomach can be distinguished based on the histological appearance of their glands and their cellular composition.

Cardia

The cardia is a circumferential ring about 3 centimeters deep distal to the gastro-esophageal junction. Its glands tend to be convoluted and are lined primarily by mucus-secreting cells that lubricate the incoming food and protect the lining of the stomach near the gastro-esophageal junction. Below the glands of the mucosal layer are the lamina propria and muscularis mucosa, which are responsible for support and folding, respectively.

Body

The body is the main part of the stomach and is bounded by the greater and lesser curvatures. Its glands are straight with limited branching and are lined by a smaller population of mucus-secreting cells than those of the cardia. The neck and isthmus contain large numbers of parietal cells whereas the base contains chief cells and enterochromaffin-like (ECL) cells that release hormones. The muscularis mucosa and submucosa are also visible.

Antrum

The antrum is the distal third of the stomach. It possesses glands with deeper pits and large amounts of coiling and branching. These glands contain many mucus-secreting cells, D-cells, and G-cells but lack parietal cells. The antrum is connected to the initial segment of small intestine by short section of stomach called the pylorus.

Small Intestine

The small intestine is responsible for the continued digestion of food and absorption of nutrients and is divided into three segments that have slightly different structures and functions. The first segment is called the duodenum which is followed by jejunum and then ileum. The appearance of each of these segments and their primary functions are described below. Reflecting its absorptive function, the surface area of the epithelium facing the lumen of the small intestine is amplified significantly at three levels.

At the cellular level, enterocytes, which digest and absorb nutrients, contain microvilli along their apical surfaces. Recall that microvilli are small projections of the cell membrane that are supported structurally by actin filaments. Microvilli increase the surface area of the apical cell membrane to generate greater capacity for digestion and absorption of nutrients.

A second level of amplification of surface area involves the the lamina propria which pushes outward into the lumen to generate finger-like projections of the epithelium and lamina propria called villi. Villi increase the number epithelial cells that are in direct contact with the lumen of the small intestine, generating greater absorptive capacity.

Finally, one region of the small intestine contains outward foldings of submucosa called Plicae circulares which creates a tree-like structure with each branch a villus.

Villi

All sections of small intestine contain villi. The region of a villus that is located more close to the lumen of the intestine contains a mix of enterocytes and goblet cells. The lamina propria supports the epithelial cells and makes up the core of the villus. Within the lamina propria is a central lymphatic vessel known as a lacteal, which is crucial for the absorption of lipids from the intestine. Blood vessels and immune cells are also prominent in the lamina propria. Villi also contain a strand of smooth muscle that cause them to move and mix the contents of the intestinal lumen.

Enterocytes digest macromolecules and absorb nutrients. As described above, they contain microvilli on their apical surface to increase its surface area and allow it to contain more digestive enzymes and channels for greater absorption of nutrients. Enzymes in the apical membrane digests disaccharides into monosaccharide and small peptides into individual amino acids. These molecules enter enterocytes through channels such as sodium-glucose co-transporter (SGLT1) and amino acid transporters.

Enterocytes also absorb many of the ions and water from the contents of the small intestine. Sodium enters enterocytes through co-transporters for glucose or amino acids and through epithelial sodium channels. Chloride enters through chloride channels or chloride-bicarbonate exchangers. Most water is drawn across the epithelial layer via osmosis and passes through paracellular pathways. Solvent drag brings potassium across the epithelium.

Goblet cells secrete mucus which protects the epithelial layer.

Crypts of Lieberkuhn

The base of a villus that is closest to the submucosa is know as the crypt of Lieberkuhn. Here, the epithelium performs several critical functions that do not involve digestion or absorption of nutrients.

The epithelium in the crypts contains cells that perform immune functions. Paneth cells, which appear spotted and eosinophilic in H&E stained samples, support the host defense against microbes by releasing several different types of antimicrobial peptides that prevent the growth of enteric pathogens. In addition, Paneth cells also nurture the stem cells of the epithelium (see below).

The epithelium of the crypts also contains enteroendocrine cells that regulate the activity of cells in other organs. For example, I cells in the duodenum and jejunum secrete a hormone called cholecystokinin which trigger cells in the pancreas to release digestive enzymes that are delivered to the lumen of the duodenum. Another type of endocrine cell in the crypt is a S cell that produces the hormone secretin. Secretin stimulates cells in the pancreas to produce bicarbonate which is also delivered to the duodenum to neutralize the acid coming from the stomach.

Lastly, the crypts contain cells that replenish all of the other cell types found in the epithelium. The epithelium of the small intestine turns over rapidly, with most cells having an estimated lifetime of 3 to 5 days. Consequently, the epithelium must constantly proliferate to replace lost cells and the crypts are where cell differentiation and division occur.

The base of the crypts contain the functional stem cells of the epithelium. The stems cells are often nestled between Paneth cells. Stem cells generate cells that commit to a specific type of epithelial cell (e.g. enterocyte, goblet cell). These lineage-committed cells, called transit amplifying cells, divide rapidly to generate a sufficient number of replacement cells in the epithelium. The extensive cell division in the crypt pushes cells upward along the epithelium. The regions of the crypt where the committed cells divide is called the transit amplifying zone. As the epithelial cells emerge from the crypt, they stop dividing and assume the physiological functions of their lineage. These cells are slowly pushed upward toward the tip of villus where most cells are lost due to apoptosis. Thus, epithelia of the villi resemble a conveyer belt where cells are born and differentiate in the base and migrate upward toward the tip as functional enterocytes or goblet cells.

Segments of the Small Intestine

The small intestine begins after the gastro-duodenal junction and is divided into duodenum, jejunum and ileum.

Duodenum

The duodenum contains the same wall layers seen in the previous portions of the GI tract: mucosa, submucosa, and muscularis externa. The mucosa and lamina propria form long villi. The epithelial cells of the mucosa contain enzymes that facilitated digestions of large macromolecules. In addition, the duodenum receives digestive enzymes produced in the pancreas.

The duodenum can be distinguished from the other segments of the small intestine by the presence of glands within its submucosa called Brunner’s glands. The cells in the glands secrete an alkaline mucus that neutralizes the pH of chyme from the stomach and protects the epithelium of the duodenum.

Jejunum

The jejunum is a region of tremendous nutrient absorption and to support this absorption creates the largest surface area of the three segments of the small intestine. This cross section through the jejunum shows prominent plicae circulares lined by numerous villi. Plicae circulares are more extensive in the jejunum compared to the duodenum and ileum. Note that while the submucosa and mucosa extend into the plicae circulares, the muscularis externa does not. Each villus is lined by an epithelium with numerous enterocytes that absorb the small molecules produced through digestion of food.

Ileum

The ileum has the shortest villi and is characterized by abundant Peyer’s patches in the submucosa. Peyer’s patches are diffuse lymphoid tissue that play an important immunological role in sampling the contents of the GI tract.

The small intestine ends with the ileo-cecal junction.

Large Intestine

The large intestine or colon processes the indigestible material that comes from the small intestine. It absorbs sodium, chloride and water to concentrate waste material that is formed into feces. The large intestine can either absorb or secrete potassium and absorbs vitamins. Structurally, the large intestine lacks villi but still has a glands with crypts. The epithelium contains a mix of absorptive cells and goblet cells but goblet cells start to predominate. Absorptive cells are responsible for taking up sodium and chloride and allowing the passage of water via osmosis. The goblet cells secrete mucus to protect the epithelium from the increasingly dehydrated feces. The lamina propria has many macrophages, plasma cells, eosinophils, and lymphoid nodules. The external muscular layers are thicker in the colon allowing it to generate more powerful peristaltic contractions to propel waste.

At higher magnification, the glandular structure in the colon is more evident. Similar to epithelium in the small intestine, the base of glands contain stem cells and transit amplifying cells that replace older cells at the top of the glands. Also visible in the slide is a lymphoid aggregate in the submucosa which helps control the bacterial population in the lumen of the large intestine.

The large intestine feeds into the rectum, which stores the feces and has a columnar epithelium with abundant goblet cells. Feces pass out of the rectum, through the anus, and out of the body. The anus is characterized by a stratified squamous epithelium that undergoes a gradual transition to skin containing sebaceous and apocrine sweat glands.

Recto-Anal Junction

The recto-anal junction features an important change in epithelial structure. The rectum is characterized by the same columnar epithelium that lines the majority of the gastrointestinal tract’s secretory and absorptive areas. The anus, on the other hand, has a stratified squamous epithelium that provides a greater deal of protection to the underlying tissue.

Mixing and Propulsion of Food

To facilitate digestion, chyme must be mixed with digestive enzymes and bile produced by the pancreas and liver, respectively. In addition, chyme must be propelled in one direction toward one end of the gastrointestinal tract in a process called peristalsis.

Mixing and peristalsis require coordinated constriction and relaxation of the lumen of the gastrointestinal tract. Constriction propels chyme while relaxation allows chyme to enter a part of the gastrointestinal tract.

To mix food, the intestine constricts when it senses the presence of a bolus of chyme while the regions immediate before and after the chyme relax. This divides the chyme into two sections, sending one backward (orad) and the other forward (caudad). The section then relaxes allowing the two masses of chyme to rejoin. The continuous splitting and rejoining chyme mixes food with enzymes from the pancreas and bile from the liver.

During peristalsis, the region of intestine just behind (orad side) a bolus of chyme constricts while the region ahead relaxes pushing the chyme forward in the caudad direction toward the end of the gastrointestinal tract. Contraction and relaxation proceed in a wave-like fashion along the intestine to continuously move chyme down the gastrointestinal tract.

Coordinated contraction and relaxation of the two smooth muscle layers surrounding the gastrointestinal serve to constrict or relax the lumen. An important structural principle is that at any given segment of the gastrointestinal tract the two layers do no contract at the same time. To constrict the lumen, the inner circular layer contracts while the outer longitudinal layer relaxes. To relax the tract, the inner layer relaxes while the outer layer contracts.

Enervation of GI Tract

Coordination of smooth muscle contraction and regulation of secretion is controlled by extensive enervation of the gastrointestinal tract. The enteric nervous system (ENS) comprises over 100 million neurons and is considered a third branch of the autonomic nervous system along with the sympathetic and parasympathetic systems. The ENS controls smooth muscle contraction and secretion by parietal cells, ECL cells and chief cells. The parasympathetic and sympathetic systems also regulate these activities.

Neurons of the ENS usually cluster in two locations in along the gastrointestinal tract. One is the myenteric or Auerbach’s plexus which is found between the two layers of smooth muscle throughout the gastrointestinal tract. The second is the submucosal plexus or Meissner’s plexus which is located in the submucosal layer only in the small and large intestine. Neurons in both plexuses contribute to coordination of smooth muscle contraction and regulation of secretion of parietal, ECL and chief cells.